Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets.

Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension

Representing serial action and perception

This article presents a review on the representational base of sequence learning in the serial reaction time task. The first part of the article addresses the major questions and challenges that underlie the debate on implicit and explicit learning. In the second part, the informational content that underlies sequence representations is reviewed. The latter issue has produced a rich and equivocal literature. A taxonomy illustrates that substantial support exists for associations between successive stimulus features, between successive response features, and between successive response-to-stimulus compounds. We suggest that sequence learning is not predetermined with respect to one particular type of information but, rather, develops according to an overall principle of activation contingent on task characteristics. Moreover, substantiating such an integrative approach is proposed by a synthesis with the dual-system model (Keele, Ivry, Mayr, Hazeltine, & Heuer, 2003)